Advances in Therapy for Urothelial and Non-Urothelial Subtype Histologies of Advanced Bladder Cancer: From Etiology to Current Development

Round 1

Reviewer 1 Report

Comments and Suggestions for Authors

The manuscript provides a detailed overview of the current classification, management, and emerging therapeutic approaches for bladder cancer subtypes. The authors effectively highlight the challenges associated with the treatment of rare histological subtypes and emphasize the importance of precision medicine. They underline the lack of robust evidence among these subtypes, lacking of clinical trials that include them. However, there are areas where the manuscript could benefit from further refinement and elaboration to enhance its clarity and impact.

 The introduction provides a robust context for the review but does not clearly state the main objectives of the manuscript. Consider explicitly stating the primary aim and scope of the review early in the introduction.

The section on antibody-drug conjugates (ADCs) and FGFR inhibitors is promising but could be expanded with more discussion of clinical outcomes, ongoing trials, and potential limitations.

The use of terms like “subtypes” and “variants” may cause confusion. Consider defining these terms clearly at the outset and using them consistently throughout.

Author Response

Reviewer 1

Comments and Suggestions for Authors

The manuscript provides a detailed overview of the current classification, management, and emerging therapeutic approaches for bladder cancer subtypes. The authors effectively highlight the challenges associated with the treatment of rare histological subtypes and emphasize the importance of precision medicine. They underline the lack of robust evidence among these subtypes, lacking of clinical trials that include them. However, there are areas where the manuscript could benefit from further refinement and elaboration to enhance its clarity and impact. 

 

1- The introduction provides a robust context for the review but does not clearly state the main objectives of the manuscript. Consider explicitly stating the primary aim and scope of the review early in the introduction.

Response: Thank you for your thoughtful suggestion. We added sentences about the primary aim and scope of the review early in the introduction.

Revisions:

Page 2, line 54-58

In this review, we aim to provide a comprehensive synthesis of the current management landscape for advanced bladder cancer—encompassing both urothelial and non-urothelial subtypes—by integrating histopathological insights, evolving therapeutic strategies, and emerging molecular targets to better inform individualized treatment approaches.

 

2- The section on antibody-drug conjugates (ADCs) and FGFR inhibitors is promising but could be expanded with more discussion of clinical outcomes, ongoing trials, and potential limitations.

Response: Thank you for the valuable suggestion. We have added paragraph to the 4. Challenges and Future Directions section for more discussion of clinical outcomes, ongoing trials, and potential limitations.

Revisions: 

Page 17, line 703-712

ADCs and FGFR inhibitors have emerged as promising therapeutic options for urothelial and non-urothelial subtypes. However, as described above, in urothelial and non-urothelial subtypes of bladder cancer, evidence evaluating the efficacy of ADCs and FGFR inhibitors remains limited, unstandardized, and generally associated with lower response rates compared to pure UC. These challenges are compounded by tumor heterogeneity, variability in antigen expression, and discrepancies in FGFR3 mutational status. To advance therapeutic strategies, large-scale prospective clinical trials, detailed molecular profiling, and the adoption of precision-targeted approaches are crucial. Ongoing re-search is investigating combination therapies—such as FGFR inhibitors paired with ADCs or immune checkpoint inhibitors—to improve outcomes [7].

 

3- The use of terms like “subtypes” and “variants” may cause confusion. Consider defining these terms clearly at the outset and using them consistently throughout.

Response: Thank you for the valuable suggestion. We have added sentences to the introduction to reduce confusion about terms like “subtypes” and “variants” and use “subtypes” consistently throughout. Table 1 was also revised accordingly.

Revisions:

Page 1-2, line 42-50, (minor: 75,113,285,478,655-656) and Table 1

The terminology “Urothelial Subtypes” refers to categories of bladder cancer that originate from urothelial cells but exhibit additional and distinct histological features beyond the conventional UC. These include UCs with mixed histological differentiation, such as squamous or glandular differentiation, or micropapillary UC. In con-trast, “Non-Urothelial Subtypes” describe bladder cancers that arise from entirely different cellular lineages and not from urothelial cells. These subtypes include squamous cell carcinoma (SCC), adenocarcinoma, and small cell carcinoma, which emerge through alternative pathways of differentiation and are distinct in both their histological appearance and cellular origin.

 

Table 1. 2022 WHO classification of invasive tumors of the urothelial tract

Main histological subtypes	Subgroups
Invasive UC subtypes	Conventional UC
	Infiltrating UC with squamous differentiation
	Infiltrating UC with glandular differentiation
	Infiltrating UC with trophoblastic differentiation
	Nested UC
	Tubular and microcystic UC
	Micropapillary UC
	Lymphoepithelioma-like UC
	Plasmacytoid UC
	Sarcomatoid UC
	Giant cell UC
	Lipid-rich UC
	Clear cell UC
	Poorly differentiated UC
Squamous cell neoplasms	Pure squamous cell carcinoma
	Verrucous carcinoma
	Squamous cell papilloma
Glandular neoplasms	Adenocarcinoma, NOS -Enteric
	Adenocarcinoma, NOS -Mucinous
	Adenocarcinoma, NOS -Mixed
	Villous adenoma
Tumors of Müllerian Type	Clear cell carcinoma
	Endometrioid carcinoma
Neuroendocrine tumors	Small cell neuroendocrine carcinoma
	Large cell neuroendocrine carcinoma
	Well-differentiated neuroendocrine tumor
	Paraganglioma
Mesenchymal tumors	Rhabdomyosarcoma
	Leiomyosarcoma
	Angiosarcoma
	Malignant inflammatory myofibroblastic tumor
	Malignant perivascular epithelioid cell tumor
	Malignant solitary fibrous tumor
Miscellaneous tumors	Epithelial tumors of the upper urinary tract
	Tumors arising in a bladder diverticulum
	Urothelial tumors of the urethra
	Malignant melanoma
	Carcinoma of Skene, Cowper, and Littre glands
	Metastatic tumors and tumors extending from other organs

Abbreviations: WHO, World Health Organization; UC, urothelial carcinoma; NOS, not otherwise specified

Reviewer 2 Report

Comments and Suggestions for Authors

This review present recent advances in management of urothelial / non-urothelial bladder cancer subtypes and try to explore the current evidence guiding the treatment and emphasize the challenges and perspectives of future therapeutic strategies. The article is well-documented, logical, and in line with the scope of this journal.

Minor issue should be modified.

In Figure 1, no scale bar was shown in image. The images from different subtype of UC are inconsistent and not aligned, which lacks the rigor of scientific research papers and affects readers' perception.

 

Author Response

Reviewer 2

This review present recent advances in management of urothelial / non-urothelial bladder cancer subtypes and try to explore the current evidence guiding the treatment and emphasize the challenges and perspectives of future therapeutic strategies. The article is well-documented, logical, and in line with the scope of this journal.

 

Minor issue should be modified.

 

In Figure 1, no scale bar was shown in image. The images from different subtype of UC are inconsistent and not aligned, which lacks the rigor of scientific research papers and affects readers' perception.

 

Response: Thank you for the valuable suggestion.

Revisions: We replaced with an image with a scale bar added. (Figure 1.)